Vemurafenib (sometimes referred to as Compound I) is a b-raf kinase inhibitor that specifically targets mutant b-Raf having the V600E mutation. Vemurafenib is commercially available as Zelboraf™, Genentech, South San Francisco, Calif. This compound is described in U.S. Pat. Nos. 7,504,509 and 7,863,288. Vemurafenib is currently approved for the treatment of V600E mutation positive metastatic melanoma and is undergoing investigation for the inhibition of several other tumors, for example, colorectal and thyroid cancers.
p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells.
The ratio of MDM2 to p53 is dysregulated in many cancers. Activation of p53 by antagonizing its negative regulator MDM2 is thus a useful strategy in treating cancer and several MDM2 antagonists are in development. For example, (4S,5R)-1-[[4-[[4,5-bis(4-chlorophenyl)-2-[4-(tert-butyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]]-carbonyl]-4-[3-(methylsulfonyl)propyl]-piperazine (referred to herein as Compound II) and 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid (referred to herein as Compound III) are in phase I clinical trials for the treatment of solid tumors. Compound II is disclosed in U.S. Pat. No. 7,851,626. Compound III is disclosed in US Pub 2010/0152190 A1. To the extent deemed necessary, both of these publications are herein incorporated by reference.
Applicants have unexpectedly found that combination therapy with vemurafenib and an MDM2 inhibitor not only is capable of overcoming resistance to vemurafenib (that is, potentiation of activity in previously vemurafenib resistant cells), but also results in improved antineoplastic effects that are significantly superior to the results obtained with each compound alone, without a significant increase in toxicity. Moreover, because these two types of compounds exert antitumor effects by affecting different cellular mechanisms, a therapeutic combination of both compounds is expected to yield improved antitumor activity in certain tumors and/or prevent or delay resistance to drug therapy.